7-Arylsulfonamido-2,3,4,5-tetrahydro-1h-benzo&#39;diazepine derivatives with 5ht6 receptor affinity for the reatment of cns disorders

ABSTRACT

The present invention relates to novel sulfonamide compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.

This invention relates to novel sulfonamide compounds havingpharmacological activity, processes for their preparation, tocompositions containing them and to their use in the treatment of CNSand other disorders.

WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WO 01/32646(SmithKline Beecham plc) disclose a series of aryl sulphonamide andsulphoxide compounds that are said to be 5-HT₆ receptor antagonists andwhich are claimed to be useful in the treatment of various CNSdisorders.

A structurally novel class of compounds has now been found which possessaffinity for the 5-HT₆ receptor. The present invention thereforeprovides, in a first aspect, a compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein:

-   -   R¹ represents hydrogen, halogen, hydroxy, cyano, nitro,        trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl,        trifluoromethanesulfonyloxy, pentafluoroethyl, C₁₋₆ alkoxy,        arylC₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇        cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆        alkylsulfonylC₁₋₆ alkyl, arylsulfonyl, arylsulfonyloxy,        arylsulfonylC₁₋₆ alkyl, C₁₋₆ alkylsulfonamido, C₁₋₆ alkylamido,        C₁₋₆ alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl,        arylsulfonamido, arylcarboxamido, arylsulfonamidoC₁₋₆ alkyl,        arylcarboxamidoC₁₋₆ alkyl, aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆        alkanoyl, or a group CONR³R⁴ or SO₂NR³R⁴, wherein R³ and R⁴        independently represent hydrogen or C₁₋₆ alkyl or together may        be fused to form a 5- to 7-membered aromatic or non-aromatic        heterocyclic ring optionally interrupted by an O or S atom;    -   R² represents hydrogen or C₁₋₆ alkyl;    -   m represents an integer from 1 to 3;    -   n represents an integer from 1 to 4;    -   A represents phenyl, naphthyl or a monocyclic or bicyclic        heteroaryl group each of which may be optionally substituted by        one or more substituents which may be the same or different, and        which are selected from those defined for R¹;    -   or solvates thereof.

Specific groups of compounds of formula (I) which may be mentioned arethose as defined above with the proviso that when A represents phenylsubstituted at the 4-position, said substituent is not trifluoromethyl,trifluoromethoxy, C₃₋₆ alkyl or C₁₋₆ alkoxy.

Further specific groups of compounds of formula (1) which may bementioned are those as defined above wherein m represents 0.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched and the groups alkoxy and alkanoyl shall beinterpreted similarly. Alkyl moieties are more preferably C₁₋₄ alkyl,eg. methyl or ethyl. The term ‘halogen’ is used herein to describe,unless otherwise stated, a group selected from fluorine, chlorine,bromine or iodine.

The term “aryl” includes phenyl and naphthyl.

The term “heteroaryl” is intended to mean a 5 or 6 membered monocyclicaromatic or a fused 8-10 membered bicyclic aromatic ring containing I to3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitableexamples of such monocyclic aromatic rings include thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl,pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fusedaromatic rings include benzofused aromatic rings such as quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl,indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.Heteroaryl groups, as described above, may be linked to the remainder ofthe molecule via a carbon atom or, when present, a suitable nitrogenatom except where otherwise indicated above.

It will be appreciated that wherein the above mentioned aryl orheteroaryl groups have more than one substituent, said substituents maybe linked to form a ring, for example a carboxyl and amine group may belinked to form an amide group.

Preferably, A is substituted by 0 to 3 substituents, more preferably 0,1 or 2 substituents. Preferably, A represents phenyl or a monocyclicheteroaryl group (such as thienyl) optionally substituted by one or morehalogen (such as chlorine or bromine, eg. 3-chlorophenyl,4-chlorophenyl, 4-bromophenyl, 5-bromophenyl, 2,3-dichlorophenyl or3,5dichlorophenyl), C₁₋₆ alkyl (such as methyl, eg. 4-methyl or ethyl,eg. 2-ethyl), C₁₋₆ alkoxy (such as methoxy, eg. 2-methoxy),trifluoromethoxy (such as 2-trifluoromethoxy) or trifluoromethyl (suchas 3-trifluoromethyl) groups.

More preferably, A represents unsubstituted phenyl or phenyl substitutedby 3-trifluoromethyl, halogen (eg. 4-chloro and 4-bromo) and/or2-trifluoromethoxy.

Most preferably, A represents phenyl di-substituted by halogen(especially 4-chloro or 4-bromo) and 2-trifluoromethoxy.

Preferably, m is 0 or 1, most preferably 0.

When m is 1, R¹ is preferably halogen (eg. 6-chlorine, 9-chlorine or9-bromine) or C₁₋₆ alkoxy (such as methoxy, eg. 8-methoxy).

Preferably, n is 0.

Preferred compounds according to the invention include examples E1-E17as shown below, or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.The present invention includes within its scope all possiblestoichiometric and non-stoichiometric forms. Preferably, the compound offormula (I) forms an acid addition salt with hydrochloric acid.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be solvated,eg. as the hydrate. This invention includes within its scopestoichiometric solvates (eg. hydrates) as well as compounds containingvariable amounts of solvent (eg. water).

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers) and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

-   -   (a) reacting a compound of formula (II)        wherein R¹, R², m and n are hereinbefore defined and P¹ is a        suitable protecting group such as acetyl, trifluoroacetyl,        t-butyloxycarbonyl, 2′,2′,2′-trichloroethoxycarbonyl, benzyl or        methyl, with a compound of formula (III)        wherein A is as hereinbefore defined and L is a suitable leaving        group, such as a halogen atom (eg. fluorine or chlorine) and        thereafter deprotecting the resultant compound; or    -   (b) deprotecting a compound of formula (I) which is protected;        and optionally thereafter    -   (c) interconversion to other compounds of formula (I).

Process (a) typically comprises the use of a suitable base such aspyridine or triethylamine in an inert solvent such as dichloromethane ortetrahydrofuran.

In process (b), examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulphonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid) or reductively (e.g.hydrogenolysis of a benzyl group or reductive removal of a2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid) asappropriate. Other suitable amine protecting groups includetrifluoroacetyl (—COCF₃) which may be removed by base catalysedhydrolysis or a solid phase resin bound benzyl group, such as aMerrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), whichmay be removed by acid catalysed hydrolysis, for example withtrifluoroacetic acid.

Process (c) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic or electrophilic aromatic substitution, ester hydrolysis oramide bond formation. Examples of process (c) include interconversionsof the groups R¹, R² and A.

Compounds of formula (II) and (III) are known in the literature or canbe prepared by analogous methods.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable saltshave affinity for the 5-HT₆ receptor and are believed to be of potentialuse in the treatment of certain CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorders, migraine,cognitive memory disorders (e.g. Alzheimers disease, age relatedcognitive decline and mild cognitive impairment), Parkinsons Disease,ADHD (Attention Deficit Disorder/Hyperactivity Syndrome), sleepdisorders (including disturbances of Circadian rhythm), feedingdisorders such as anorexia and bulimia, panic attacks, withdrawal fromdrug abuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Compounds of the invention are alsoexpected to be of use in the treatment of certain GI (gastrointestinal)disorders such as IBS (Irritable Bowel Syndrome). Compounds of theinvention are also expected to be of use in the treatment of obesity.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of the abovedisorders. In particular the invention provides for a compound offormula (I) or a pharmaceutically acceptable salt thereof, for use inthe treatment of depression, anxiety, obesity and cognitive memorydisorders

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment or prophylaxis ofthe above disorders.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. The present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 200 mg, for example 20 to 40 mg; and such unitdoses will preferably be administered once a day, althoughadministration more than once a day may be required; and such therapymay extend for a number of weeks or months.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1

3-t-Butyloxycarbonyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo [d]azepine (D1)

A solution of di-t-butyl dicarbonate (19.3 g, 88.2 mmol) indichloromethane (150 ml) was added over 0.5 h to a stirred, ice-cooledsolution of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (11.3 g, 58.8mmol) (for synthesis see Pecherer et al., J.Het. Chem., 1971, 8, 779)and triethylamine (12.3 ml, 88.2 mmol) in dichloromethane (150 ml) underargon. The solution was warmed to ambient temperature and stirred for 18h. The reaction mixture was then washed with water (2×400 ml), dried(MgSO₄) and concentrated in vacuo to an oily solid. The solid waspurified by chromatography over silica gel eluting with a solventgradient of ethyl acetate/hexane to afford the title compound (D1) as acolourless solid (9.1 g, 31.1 mmol, 53%). δH (CDCl₃, 400 MHz) 1.49 (9H,s), 3.00 (4H, br s), 3.58 (4H, br s), 7.27-7.29 (1H, br d), 7.98-8.00(2H, br, m).

Description 2

7-Amino-3-t-butyloxycarbonyl-2,3,4,5tetrahydro-1H-benzo[d]azepine (D2)

A solution of3-t-butyloxycarbonyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D1)(8.0 g, 27.4 mmol) in ethanol (250 ml) was stirred with 10% palladium oncarbon (1.3 g) for 20 h under one atmosphere of hydrogen at ambienttemperature. The reaction mixture was filtered to remove the catalystand the filtrate was evaporated in vacuo to yield the title compound(D2) as a colourless oil (7.0g, 26.6mmol, 97%). δH (CDCl₃, 400 MHz) 1.48(9H, s), 2.78 (4H, br s), 3.51 (6H, br s), 6.45-6.48 (2H, m), 6.89 (1H,d, J=7.5 Hz).

Description 3

3-t-Butyloxycarbonyl-7-(3-trifuoromethyl)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D3)

A solution of7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D2)(512 mg, 1.95 mmol) in dichloromethane (20 ml) was treated successivelywith pyridine (1 ml) and 3-trifluoromethylbenzenesulfonyl chloride[Lancaster] (2.15 mmol, 520 mg) with stirring. After 2 hours, water (1ml) was added, and the mixture stirred vigorously for a further 2 h thenthe solvents evaporated. The residue was dissolved in ethyl acetate (100ml) and washed successively with 5% aq. citric acid (50 ml), water (50ml) and brine (50 ml) then dried (MgSO₄) and evaporated in vacuo. Theresidue was purified by flash chromatography (gradient of ethylacetate/hexane) on silica gel to afford the title compound (D3) as aclear oil (910 mg, 99%).

δH (CDCl₃, 400 MHz) 1.47 (9H, s), 2.77-2.83 (4H, m), 3.48-3.49 (4H, m),6.8 (1H, br s), 6.9 (1H, br s), 6.99 (1H,d), 7.23 (1H, s), 7.60 (1H,app.t), 7.79 (1H, d), 7.95 (1H, d), 7.98 (1H, s).

Description 4

3-t-Butyloxycarbonyl-7-phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D4)

The title compound (D4) was prepared in 72% yield as described inDescription 3, by treatment of7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D2)with phenyl sulfonyl chloride.

δH (D6-DMSO), 400 MHz) 1.37 (9H, s), 2.70 (4H, br, s), 3.36 (4H, br, s),6.83-6.85 (2H, m), 6.97 (1H, d, J=8.3 Hz), 7.52-7.60 (3H, m), 7.75 (2H,d, J=7.2 Hz), 10.2 (1H, s).

Description 5

7-Nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D5)

To a stirred, ice-cooled solution of7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (29 g, 0.15 mol) (forsynthesis see Pecherer et al., J.Het. Chem., 1971, 8, 779) indichloromethane (1 litre) was slowly added triethylamine (41.8 ml, 0.30mol) followed by dropwise addition of trifluoroacetic anhydride (42.4ml, 0.30 mol). The resulting mixture was allowed to stir and warm toambient temperature over 18 h before being poured onto ice. The organicphase was separated and the aqueous layer extracted with dichloromethane(200 ml). The combined organic phases were then washed with saturatedaqueous sodium hydrogen carbonate (600 ml), brine (600 ml) and thendried (MgSO₄) and evaporated in vacuo. The crude residue (59 g) waspurified by column chromatography on silicagel eluting with ethylacetate/ hexane (1:4) to afford the title compound (D5) as a yellowsolid (37 g, 0.128 mol, 86%).

δH (CDCl₃, 400 MHz) 3.08-3.13 (4H, m), 3.74-3.84 (4H, m), 7.31-7.36 (1H,m), 8.03-8.07 (2H, m).

Description 6

7-Amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D6)

A mixture of7-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D5) (37g, 0.128 mmol) and 10% palladium on carbon (5 g) in ethanol (200 ml) and1,4-dioxane (600 ml) was stirred with hydrogen at atmospheric pressureand room temperature for 18 h. The mixture was filtered and the filtrateconcentrated in vacuo to a solid which was stirred with hexane (200 ml)for 1 h. Filtration of the mixture gave the title compound (D6) as asolid (32.5 g, 0.126 mmol, 98%).

δH (CDCl₃, 400 MHz) 2.84-2.89 (4H, m), 3.05 (2H, br, s), 3.63-3.68 (2H,m), 3.71-3.76 (2H, m), 6.48-6.51 (2H, m), 6.91-6.95 (1H, m).

Description 7

7-(4Bromo-2-trifluoromethoxy)phenylsulfonamido-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D7)

To a stirred solution of7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D2)(23.4 g, 89.3 mmol) in pyridine (60 ml) and dichloromethane (140 ml) at5° C. was added 2-trifluoromethoxy-4-bromo-benzenesulfonyl chloride(33.4 g, 98.2 mmol) in dichloromethane (20 ml) over 30 mins. Thesolution was then stirred at room temperature for 18 hours. The solventswere removed and the residue purified by chromatography on silica using20% ethyl acetate in hexane. The crude product was recrystallised fromethyl acetate/hexane to afford the title compound (D7) as a pale yellowsolid (30.5 g, 60%).

δH (CDCl₃, 400 MHz), 1.46 (9H, s), 2.79 (4H, m), 3.48 (4H, m), 6.63 (1H,s), 6.80 (1H, br s), 6.84 (1H, s), 6.96 (1H, d, J=8.08 Hz), 7.47 (1H, ddJ=8.4, 1.6 Hz), 7.52 (1H, s), 7.79 (1H, d J=8.4 Hz).

Description 8

7-(4-Bromo-2-trifluoroethoxy)phenylsulfonamido-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D8)

A solution of 4-bromo-2-trifluoromethoxybenzene sulfonyl chloride (42.4g, 125 mmol) in dichloromethane (100 ml) was added over 20 minutes to astirred solution of7-amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D6)(32.3 g, 125 mmol) and pyridine (30.2 ml, 375 mmol) in dichloromethane(150 ml) at room temperature under argon. After 18 h the solution wasdiluted with dichloromethane (750 ml) and washed successively with water(1 litre), 1M hydrochloric acid (2×1 litre) and brine (1 litre). Theorganic extract was dried (MgSO₄) and concentrated in vacuo to a red oilwhich was purified by column chromatography over silicagel eluting witha gradient of ethyl acetate/hexane to afford the title compound (D8) asa colourless oil (56 g, 100 mmol, 80%)

δH (CDCl₃, 400 MHz) 2.87-2.91 (4H, m), 3.62-3.65 (2H, m), 3.70-3.73 (2H,m), 6.67 (1H, br, s), 6.83-6.86 (1H, m), 6.91 (1H, d, J=2.2 Hz),6.99-7.03 (1H, m), 7.48-7.58 (2H, m), 7.79-7.82 (1H, m).

Found [MH]⁺ 561/563 (C₁₉H₁₅BrF₆N₂O₄S)

Description 9

7-(4-Chloro-2-trifluoromethoxy)phenylsulfonamido-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D9)

An efficiently stirred mixture of7-(4-bromo-2-trifluoromethoxy)phenylsulfonamido-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D8) (55 g, 98 mmol) and copper (I) chloride (193 g, 1.94 mol) in dryN,N-dimethylformamide (540 ml) was heated at 120° C. for 24 h underargon. The mixture was cooled to ambient temperature then the solidfiltered, and washed with dry N,N-dimethylformamide (2×100 ml). To thefiltrate and washings was added fresh copper (I) chloride (48 g, 485mmol) and the stirred mixture reheated at 120° C. for 18 h under argon.The mixture was cooled to ambient temperature and the solid was filteredand washed with dichloromethane (6×200 ml). The filtrate and washingswere concentrated in vacuo and the residue re-concentrated with toluene(2×750 ml). The residue was then stirred with dichloromethane (250 ml)and the whole mixture filtered through kieselguhr. The filtrate wasconcentrated in vacuo and the residue partially purified by columnchromatography over silicagel eluting with dichloromethane to affordcrude title product (D9) as a foam (42.8 g). This material wascrystallised by dissolving in diethyl ether (150 ml) at room temperatureand adding hexane (150 ml) with stirring and leaving to fullycrystallize for 2 days. The colourless crystals were filtered off andidentified as the title compound (D9) (24 g, 46.4 mmol, 47%). A secondcrop of the product (D9) (7.4 g, total yield=31.4 g, 60.7 mmol, 62%) wasisolated from the filtrate by concentrating the filtrate andre-chromatographing the residue over silicagel (acetone/toluenegradient) followed by crystallisation from diethyl ether/hexane.

δH (CDCl₃, 400 MHz) 2.87-2.91 (4H, m), 3.62-3.65 (2H, m), 3.70-3.73 (2H,m), 6.71 (1H, s), 6.83-6.87 (1H, m), 6.90 (1H, d, J=2.3 Hz), 6.99-7.03(1H, m), 7.31-7.39 (2H, m), 7.87-7.90 (1H, m).

Found [MH]⁺ 517/519 (C₁₉H₁₅ClF₆N₂O₄S)

Description 10

7-Aminochloro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D10)

7-Amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D2)(1.57 g, 6 mmol) was dissolved in acetonitrile (30 ml) and treated withN-chlorosuccinimide (895 mg, 6.5 mmol) at 0° C. and the stirred mixtureallowed to warm to room temperature for 14 hours. Saturated aqueoussodium sulphite (5 ml) was added and the mixture evaporated. The residuewas triturated with diethyl ether (2×100 ml), and the combined organicphase dried (MgSO₄), filtered and evaporated. The residue was subjectedto flash chromatography on silica gel, eluting with a mixture of ethylacetate and hexane to afford the title compound (D10) as a white solid;yield 305 mg.

δH (CDCl₃, 400 MHz) 1.46(9H, s), 2.82 (2H, m), 3.12 (2H, m), 3.53 (4H,m), 4.02 (2H, s), 6.56 (1H, d), 6.82 (1H, d).

Description 11

3-Acetyl-6-iodo-8nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D11)

To a stirred solution of3-acetyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine [J. Heterocyl.Chem. (1971), 8(5), 779-783] ( 2.71 g, 11.6 mmol) intrifluoromethane-sulfonic acid (15 ml) at room temperature was addedN-iodosuccinimide (3.38 g, 15 mmol), portionwise over 1 hour, then themixture stirred for 2 days. The mixture was poured onto ice andextracted with dichloromethane. After separating, the organic layer waswashed with sodium thiosulfate solution, then brine and dried overmagnesium sulfate. After filtration, the solvent was evaporated in vacuoto afford the title compound (D11), (2.74 g, 69%).

δH (CDCl₃, 400 MHz), 2.17,2.16 (3H, 2s), 3.10 (2H, m), 3.30 (2H, m),3.65 (2H, m), 3.76 (2H, m), 8.00 (1H, 2d, J=2.2 Hz), 8.60 (1H, 2d, J=2.2Hz).

Description 12

6-Iodo-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D12)

A mixture of3-acetyl-6-iodo-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D1) (2.74g, 7.59 mmol) and hydrochloric acid ( 36%, 250 ml) was heated at refluxfor 2 days, cooled, filtered and evaporated to dryness. The residue wasredissolved in water, treated with sodium bicarbonate and extracted withdichloromethane. The organic layer was dried, filtered and evaporated toafford the title compound (D12) (2.2 g, 91%).

δH (DMSO-d6, 400 MHz), 2.50 (4H, m), 3.04 (2H, m), 3.22 (2H, m), 8.02(1H, d, J=2.4 Hz), 8.40 (1H, d, J=2.4 Hz).

Description 13

6-Iodo-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D13)

To a stirred solution of6-iodo-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D12) (2.2 g, 6.9mmol) in dichloromethane (40 ml), was added 2 equivalents of polymersupported Hunig's base [Argonault Tech.] (3.83 mmol/g; 3.6 g, 13.8mmol). After cooling to 5° C., trifluoroacetic anhydride (1.6 g, 7.61mmol) was added dropwise, then stirred at room temperature for 18 hours.After filtration, the solution was washed with water then dried overmagnesium sulfate. After filtration, the solvent was removed and theresidue purified by chromatography on silica using 25% diethyl ether inhexane to afford the title compound (D13) (2.56 g 90%).

δH (CDCl₃, 400 MHz) 3.17 (2H, m), 3.38 (2H, m), 3.75 (4H, m) 8.01 (1H,m) 8.61 (1H, m).

Description 14

6Chloro-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D14)

A mixture of6-iodo-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D13) (222 mg, 0.5 mmol), copper (I) chloride (362 mg, 3.65 mmol) anddimethyl formamide (5 ml) were heated to 110° C. for 18 hours withstirring. The solvent was removed and the residue purified bychromatography on silica using 25% diethyl ether in hexane to afford thetitle compound (D14), (130 mg, 75%)

δH (CDCl₃, 400 MHz) 3.15 (2H, m), 3.48 (2H, m), 3.76 (2H, m), 3.82 (2H,m), 7.95 (1H, m), 8.19 (1H, m).

Description 15

6Bromo-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D15)

Prepared from6-iodo-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D13) and copper (I) bromide in a similar manner to Description 14, in41% yield.

δH (CDCl₃, 400 MHz) 3.18 (2H, m), 3.37 (2H, m), 3.60-3.85 (4H, m),7.97-8.06 (1H, m), 8.36-8.37 (1H, m).

Description 16

8-Amino-6-chloro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D16)

6-Chloro-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D14) (1.7 g, 5.27 mmol), was dissolved in methanol (20 ml) and treatedwith 6 equivalents of titanium trichloride (30% solution in 2N HCl, 12.3ml, 5.27 mmol) at room temperature with stirring, which was continuedfor a further hour. The reaction was treated with dropwise 30% hydrogenperoxide until the purple colour was extinguished, toluene added and thesolvent removed. A saturated solution of sodium acetate in methanol wasadded until the pH rose to ˜5 then the solvent was removed. The residuewas purified by chromatography on silica using 20-50% diethyl ether inhexane to afford the title compound (D16) (975 mg, 63%).

δH (CDCl₃, 400 MHz) 2.89 (2H, m), 3.11 (2H, m), 3.5 (2H br.s), 3.63-3.76(4H, m), 6.38 (1H, m), 6.62 (1H, m).

Description 17

8-Amino-6bromo-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D17)

Prepared from6-bromo-8-nitro-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D15) in a similar manner to Description 16, in 34% yield.

δH (CDCl₃, 400 MHz) 2.0 (2H, br.s) 2.89 (2H, m), 3.16 (2H, m), 3.64-3.76(4H, m), 6.42 (1H, m) 6.81 (1H, m).

Description 18

7-Hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D18)

7-Hydroxybenzazepine [WO 00/21951] (40 g, 0.15 mol), was dissolved inglacial acetic acid (400 ml) and added dropwise to a mixture of glacialacetic acid (200 ml), acetic anhydride (20 ml) and 70% nitric acid (16g). The reaction temperature was maintained at 10° C. using an ice bath.Following addition, the mixture was allowed to warm to ambient andstirrer for a further 2 hours. The mixture was poured into ice/water (1litre) and dichloromethane (2 litres) added. The organic phase wasseparated and neutralised to pH6 by addition of saturated sodiumbicarbonate solution. The organic phase was separated, dried (MgSO₄) andpurified by chromatography [Biotage Flash 75, 2 Kg silica cartridge]using ethyl acetate and hexane as eluents to give the title compound(D18) in 52% yield.

δH (CDCl₃, 400 MHz) 1.48 (9H, s), 2.89 (4H, m), 3.56 (4H, m), 6.92 (1H,s), 7.84 (1H, s), 10.5 (1H, br.s).

Description 19

7-Methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D19)

A mixture of7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D18) (49 g, 0.16 mol), methyl iodide (12.4 ml),potassium carbonate (27.4 g) in N,N-dimethylformamide (400 ml) wasstirred at room temperature for 16 hours. The mixture was poured intowater (300 ml) and extracted with diethyl ether (3×300 ml), the combinedorganic phases washed with brine (50 ml) and dried over MgSO₄ to affordthe title compound (D19) in 96% yield.

δH (CDCl₃, 400 MHz) 1.49 (9H, s), 2.88 (2H, m), 2.94 (2H, m), 3.57 (4H,m), 3.94 (3H, s), 6.84 (1H, s), 7.67 (1H, s).

Description 20

8-Amino-7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D20)

A solution of7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D19) (25 g, 78 mmol) in ethanol (700 ml) was treatedwith 5% palladium on charcoal (5 g) and hydrogenated at 50 psi for 1hour. The catalyst was removed by filtration under argon and thesolution evaporated to give the title compound (D20) as a white solid in96% yield.

δH (CDCl₃, 400 MHz) 1.48 (9H, s), 2.76 (4H, m), 3.51 (4H, m), 3.65 (2H,brs), 3.82 (3H, s), 6.50 (1H, s), 6.55 (1H, s).

Description 21

7-(3,5-Dichloro-2-methoxy-benzenesulfonylamino)-8methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D21)

8-Amino-7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D20) (80 mg) was dissolved in pyridine (0.5 ml),cooled to 0° C. and treated with 3,5-dichloro-2-methoxy-benzenesulfonylchloride (110 mg, 0.41 mmol). After 16 hours, the solution was treatedwith methanol-water 1:1 (1 ml) and evaporated. The residue was subjectedto chromatography on silicagel, eluting with hexane and diethyl ether togive the title compound (D21) in 87% yield.

δH (CDCl₃, 400 MHz) 1.46 (9H, s), 2.78 (4H, m), 3.48 (4H, m), 3.71 (3H,s), 3.87 (3H, s), 6.53 (1H, brs), 7.22 (1H, s), 7.46 (2H, app.s), 7.49(1H, s).

Description 22

7-(4-Bromo-2-trifluoromethoxy-benzenesulfonylamino)-6chloro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert butyl ester (D22)

A solution of7-amino-6-chloro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D10) (0.25 mmol, 75 mg) in dichloromethane (2 ml) wastreated with 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (135 mg0.4 mmol) in dichloromethane (2 ml) and pyridine (0.2 ml). After 14hours, the solution was treated with water (0.5 ml) and evaporated thenthe residue purified by flash chromatography on silicagel, eluting withdiethyl ether and hexane to afford the title compound (D22) as a whitesolid.

δH (CDCl₃, 400 MHz) 1.42 (9H, s), 2.85 (2H, m), 3.08 (2H, m), 3.48 (4H,m), 6.94 (1H, d), 7.33 (2H, m), 7.48 (2H, m), 7.85 (1H, d).

EXAMPLE 12,3,4,5-Tetrahydro-7-(3-trifluoromethyl)phenylsulfonamido-1H-benzo[d]azepine,hydrochloride (E1)

A suspension of3-t-butyloxycarbonyl-7-(3-trifluoromethyl)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D3) (910 mg, 1.93 mmol) in hydrochloric acid (40 ml, 4M in 1:1water:1,4-dioxane) was warmed to 60° C. for 1 hour. The now clearsolution was concentrated in vacuo and the residue crystallised frommethanol/ether to afford the title compound (E1) as a pale brown solid(700 mg, 89%).

δH (MeOH, 400 MHz) 3.05-3.09 (4H, m), 3.22-3.26 (4H, m), 6.94 (1H, dd,J=2.1, 8.1 Hz), 7.03 (1H, d, J=2.1 Hz), 7.12 (1H, d, J=8.1 Hz), 7.73(1H, app.t, J=7.9 Hz), 7.91 (1H, J=7.8 Hz), 7.98 (1H, s), 8.03 (1H, d,J=7.9 Hz).

Found [MH]⁺ 371 (C₁₇H₁₇F₃N₂O₂S).

EXAMPLE 2 7-Phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine,hydrochloride (E2)

The title compound (E2) was prepared in 90% yield as described inExample 1, from3-t-butyloxycarbonyl-7-phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D4).

δH (D6-DMSO, 400 MHz) 2.98 (4H, br, s), 3.08 (4H, br, s), 6.87-6.93 (2H,m), 7.04 (1H, d, J=8.1 Hz), 7.53-7.63 (3H, m), 7.77 (1H, d, J=7.3 Hz),930 (2H, br, s), 10.35 (1H, br, s).

Found [MH]⁺ 303 (C₁₆H₁₈N₂O₂S).

EXAMPLES 3-5 E3-E5

Examples E3-E5 were prepared by a two step process, using theappropriate aryl sulfonyl chloride with7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D2)in a similar manner to that described in Description 3, followed by adeprotection step in a similar manner to that described in Example 1.

Example A [MH]⁺ Formula E3 3-chlorophenyl 337/339 C₁₆H₁₇ClN₂O₂S E45-bromo-2-thienyl 387/389 C₁₄H₁₅BrN₂O₂S₂ E5 4-methylphenyl 317C₁₇H₂₀N₂O₂S

EXAMPLE 67-(4-Bromo-2-trifuoromethoxy)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6)

Prepared in an analogous procedure to E1 from7-(4-bromo-2-trifluoromethoxy)phenylsulfonamido-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(obtained in an analogous manner to that of D3 using4-bromo-2-trifluoromethoxybenzenesulfonyl chloride).

Found [MH]⁺ 465/467 (C₁₇H₁₆BrF₃N₂O₃S).

EXAMPLES 7-9 E7-E9

Examples E7-E9 were prepared by a two step process, using theappropriate aryl sulfonyl chloride with7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (D2)in a similar manner to that described in Description 3, followed by adeprotection step in a similar manner to that described in Example 1.

E7 2,3-dichlorophenyl 371/373 C₁₆H₁₆Cl₂N₂O₂S E83,5-dichloro-2-methoxyphenyl 401/403 C₁₇H₁₈Cl₂N₂O₂S E94-bromo-2-ethylphenyl 409/411 C₁₈H₂₁BrN₂O₂S

EXAMPLE 107(4-Chloro-2-trifluoromethoxy)phenylsulfonamido-2,3,5-tetrahydro-1H-benzo[d]azepine(E10)

Prepared from7-(4-bromo-2-trifluoromethoxy)phenylsulfonamido-3-triflouroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(obtained by treatment of E6 with trifluoroacetic anhydride in thepresence of pyridine as a base) by reaction with copper (I) chloride inN,N-dimethylformamide at reflux, followed by removal of thetrifluoroacetyl group using aqueous ammonia.

Found [MH]⁺ 421/423 (C₁₇H₁₆ClF₃N₂O₃S).

EXAMPLE 117-(4Bromo-2-trifluoromethoxy)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine,hydrochloride (E11)

7-(4-Bromo-2-trifluoromethoxy)phenylsulfonamido-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D7) ( 30.2 g, 53.5 mmol) in dioxane (175 ml) and 4N hydrochloric acid(175 ml) was heated to 90° C. with stirring. After 90 mins a solutionwas formed and the solvents were removed in vacuo. The residue wasrecrystallised from isopropanol to afford the title compound (E11) (23.6g, 88%).

δH (MeOd₄, 400 MHz) 3.04 (4H, m), 3.22 (4H, m), 6.92 (1H, dd, J=2.4 Hz,8 Hz), 7.01 (1H, d, J=2.4 Hz), 7.08 (1H,d, J=8 Hz), 7.64, (2H, m), 7.88,(1H, d, J=8.8 Hz).

Found [MH]⁺ 465/467 (C₁₇H₁₆BrF₃N₂O₃S)

m.p. 231-233° C.

EXAMPLE 127-(4-Chloro-2-trifluoromethoxy)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine,hydrochloride (E12)

To a stirred suspension of7-(4-chloro-2-trifluoromethoxy)phenylsulfonamido-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(D9) (30.3 g, 58.6 mmol) in methanol (750 ml) was added 32% ammoniasolution (75 ml) and the resulting solution stirred at room temperaturefor 24 h. The reaction mixture was then evaporated in vacuo, then theresidue was suspended in toluene (800 ml) and solvent evaporated invacuo. The residue was again suspended in toluene (800 ml) and solventevaporated in vacuo. To the resulting colourless residue was addeddiethyl ether (400 ml) and the mixture stirred for 30 minutes beforebeing filtered and dried in vacuo at 50° C. To a suspension of thismaterial in dichloromethane (250 ml) was added 1M HCl/diethyl ether (123ml) followed by methanol (50 ml). The resulting solution wasconcentrated to an oil and to this added dichloromethane (100ml)/diethyl ether (300 ml) to give fine white crystals. The crystalswere filtered, washed with dichloromethane/diethyl ether (1:3) (2×75 ml)and diethyl ether (2×75 ml) before being dried in vacuo. The materialwas then recrystallised from iso-propanol to afford the desired compoundas a white solid (21.8 g, 81%).

δH (DMSO-d₆, 400 MHz) 2.99-3.01 (4H, m), 3.08 (4H, br s), 6.86 (1H, dd,J=8.1 Hz, 2.3 Hz), 6.94 (1H, d, J=2.2 Hz), 7.07 (1H, d, J=8.2 Hz),7.66-7.70 (2H, m), 7.97 (1H, d, J=8.5 Hz), 9.37 (2H, br s), 10.70 (1H,br s).

Found [MH]⁺ 420/422 (C₁₇H₁₆ClF₃N₂O₃S)

m.p. 210-211° C.

EXAMPLES 13-15 E13-E15

Examples E13-E15 were prepared by treatment of the appropriatetrifluoroacetyl protected aminobenzo[d]azepine derivative (D16 for E13and E14 and D17 for E15) with the required arylsulfonyl chloride in ananalogous manner to the process described in D8, followed by treatmentof the product with aqueous ammonia (2M), and subsequent purified byrecrystallisation of their respective hydrochlorides.

Example R¹ A [MH]⁺ Formula E13 9-Cl phenyl 337 C₁₆H₁₇ClN₂O₂S E14 9-Cl(3-trifluoromethyl) 405 C₁₇H₁₆ClF₃N₂O₂S phenyl E15 9-Br phenyl 381/383CC₁₆H₁₇BrN₂O₂S

EXAMPLE 167-(4Bromo-2-trifluoroethoxy-benzenesulfonylamino)-6chloro-1,2,4,5-tetrahydro-benzo[d]azepineHydrochloride (E16)

Prepared from7-(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-6-chloro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert butyl ester (D22) by an analogous method to that described forExample 1.

δH (MeOH₄, 400 MHz) 3.15-3.47 (8H, m), 7.15 (1H, d), 7.39 (1H, d), 7.65,(2H, m), 7.89, (1H, d).

δH (MeOH-d₄, 400 MHz) 3.15-3.47 (8H, m), 7.17 (1H, d), 7.37 (1H, d),7.65, (2H, m), 7.82, (1H, d).

Found [MH]⁺ 499, 501, 503 (C₁₇H₁₅BrCIF₃N₂O₃S)

EXAMPLE 173,5-Dichloro-2-methoxy-N-(8methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamidehydrochloride (E17)

Prepared from7-(3,5-dichloro-2-methoxy-benzenesulfonylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3carboxylicacid tert-butyl ester (D21) by an analogous method to that described forExample 1.

δH (MeOD, 400 MHz) 2.99 (m, 4H), 3.14 (m, 4H), 3.55 (3H, s), 3.74 (3H,s), 6.70 (1H, s), 7.18 (1H, s), 7.52 (1H, s), 7.57 (1H, s)

Found [MH]⁺ 431, 433, 435 (C₁₈H₂₀Cl₂N₂O₄S)

Pharmacological Data

Compounds can be tested following the procedures outlined in WO98/27081.The compounds of Examples E1-E17 were tested and showed good affinityfor the 5-HT₆ receptor, having pKi values >8 at human cloned 5-HT₆receptors. More specifically, the compounds of Examples 6 and 10demonstrated pKi values >8.5 at human cloned 5-HT₆ receptors.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein: R¹ represents hydrogen, halogen, hydroxy, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl,trifluoromethanesulfonyloxy, pentafluoroethyl, C₁₋₆ alkoxy, arylC₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl,arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl, C₁₋₆alkylsulfonamido, C₁₋₆ alkylamido, C₁₋₆ alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆alkylamidoC₁₋₆ alkyl, arylsulfonamido, arylcarboxamido,arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl, aroyl, aroylC₁₋₆alkyl, arylC₁₋₆ alkanoyl, or a group CONR³R⁴ or SO₂NR³R⁴, wherein R³ andR⁴ independently represent hydrogen or C₁₋₆ alkyl or together may befused to form a 5- to 7-membered aromatic or non-aromatic heterocyclicring optionally interrupted by an O or S atom; R² represents hydrogen orC₁₋₆ alkyl; m represents an integer from 1 to 3; n represents an integerfrom 1 to 4; A represents phenyl, naphthyl or a monocyclic or bicyclicheteroaryl group each of which may be optionally substituted by one ormore substituents which may be the same or different, and which areselected from those defined for R¹; or solvates thereof:
 2. A compoundof formula (I) as defined in claim 1 which is2,3,4,5-Tetrahydro-7-(3-trifluoromethyl)phenylsulfonamido-1H-benzo[d]azepine;7-Phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine:2,3,4,5-Tetrahydro-7-(3-chloro)phenylsulfonamido-1H-benzo[d]azepine:2,3,4,5-Tetrahydro-7-(5-bromo-2-thienyl)sulfonamido-1H-benzo[d]azepine;2,3,4,5-Tetrahydro-7-(4-methyl)phenylsulfonamido-1H-benzo[d]azepine;7-(4-Bromo-2-trifluoromethoxy)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine;2,3,4,5-Tetrahydro-7-(2,3-dichloro)phenylsulfonamido-1H-benzo[d]azepine;2,3,4,5-Tetrahydro-7-(3,5-dichloro-2-methoxy)phenylsulfonamido-1H-benzo[d]azepine;2,3,4,5-Tetrahydro-7-(4-bromo-2-ethyl)phenylsulfonamido-1H-benzo[d]azepine:7-(4-Chloro-2-trifluoromethoxy)phenylsulfonamido-2,3,4,5-tetrahydro-1H-benzo[d]azepine;7-(Benzenesulfonylamino)-9-chloro-1,2,4,5-tetrahydro-benzo[d]azepine;7-(3-trifluoromethyl-benzenesulfonylamino)-9-chloro-1,2,4,5-tetrahydro-benzo[d]azepine;7-(Benzenesulfonylamino)-9-bromo-1,2,4,5-tetrahydro-benzo[d]azepine;7-(4-Bromo-2-trifluoromethoxy-benzenesulfonylamino)-6-chloro-1,2,4,5-tetrahydro-benzo[d]azepine;3,5-Dichloro-2-methoxy-N-(8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition which comprises a compound according to claim 1 and apharmaceutically acceptable carrier or excipient.
 4. A method oftreating depression, anxiety, Alzheimers disease, age related cognitivedecline, ADHD, obesity, mild cognitive impairment and schizophreniawhich comprises administering a safe and therapeutically effectiveamount to a patient in need thereof of a compound as defined in claim 1or a pharmaceutically acceptable salt thereof. 5-14. (cancelled).